The CDH1 gene is a fundamental component of human genetics, providing instructions for E-cadherin. This protein plays a significant role in maintaining the structure and integrity of tissues throughout the body. Mutations in the CDH1 gene can lead to a dysfunctional E-cadherin protein, which can have substantial health implications.
The CDH1 Gene and Its Function
The CDH1 gene is found on chromosome 16 and provides instructions for E-cadherin, a protein crucial for cell-to-cell adhesion. E-cadherin acts like a “molecular glue,” helping neighboring cells stick together to form organized tissues. This adhesive function is especially important in epithelial cells, which line various surfaces and cavities of the body.
E-cadherin also participates in cellular signaling pathways. It helps regulate cell growth, differentiation, and movement. The protein is also involved in the delicate balance of cell proliferation and the process of programmed cell death.
When a mutation occurs in the CDH1 gene, the E-cadherin protein can become abnormal. This disruption compromises normal cell adhesion, leading to cells that are less tightly bound. The loss of functional E-cadherin can allow cells to grow and divide without proper control, making it easier for them to detach and spread from their original location.
Conditions Linked to CDH1 Mutations
Germline mutations in the CDH1 gene are primarily associated with an increased risk of specific hereditary cancers. These conditions are inherited in an autosomal dominant pattern, meaning that inheriting just one copy of the mutated gene is sufficient to increase an individual’s risk. Each child of an affected parent has a 50% chance of inheriting the mutated gene.
Hereditary Diffuse Gastric Cancer (HDGC) is the most significant condition linked to CDH1 mutations. This aggressive form of stomach cancer is characterized by its diffuse growth pattern, making early detection challenging. Lifetime risk estimates for individuals with a CDH1 mutation range from 37% to 70% for males and 25% to 83% for females by age 80. The average age of HDGC diagnosis is often younger than sporadic gastric cancer, sometimes occurring as early as the teens or twenties.
Another significant association for females with CDH1 mutations is Hereditary Lobular Breast Cancer (HLBC). This type of breast cancer is distinct from other forms and is also linked to the dysfunctional E-cadherin protein. The estimated lifetime risk for women with a CDH1 mutation to develop HLBC ranges from approximately 37% to 68% by age 80. While these are the primary associations, researchers continue to investigate whether CDH1 mutations increase the risk for other cancers, though current findings are not conclusive. Not everyone with a CDH1 mutation will develop cancer, but their risk is substantially elevated compared to the general population.
Genetic Testing and Management Approaches
Genetic counseling and testing for CDH1 mutations are recommended for individuals with a family history of HDGC or multiple cases of lobular breast cancer, particularly those diagnosed at a younger age. The process typically involves an initial consultation with a genetic counselor who reviews personal and family medical history. Following this, a blood or saliva sample may be collected for genetic analysis.
A positive test result for a CDH1 mutation has implications not only for the individual but also for their relatives. Genetic counselors play a role in interpreting these results and discussing the option of cascade testing for other family members. Understanding the presence of a mutation helps inform strategies for managing the elevated cancer risks.
For Hereditary Diffuse Gastric Cancer, prophylactic total gastrectomy, which involves the complete surgical removal of the stomach, is often recommended as the most effective preventative measure. This procedure is considered due to the aggressive nature of HDGC and the difficulty in detecting it early through less invasive methods. It significantly reduces the risk of developing gastric cancer. For individuals who choose to defer or are not candidates for prophylactic surgery, regular endoscopic surveillance is an option. This involves frequent examinations of the stomach lining with specific biopsy protocols to attempt to detect any microscopic changes. However, this surveillance has limitations because the diffuse nature of HDGC can make cancerous cells difficult to identify visually and through biopsies.
For managing the risk of Hereditary Lobular Breast Cancer, increased surveillance is recommended for females with a CDH1 mutation. This typically includes regular mammograms and annual breast MRI screenings, often starting around age 30. These imaging techniques aim to detect any changes at an earlier stage. In some instances, prophylactic mastectomy may also be considered to reduce risk. Family planning considerations, such as preimplantation genetic diagnosis (PGD), can also be discussed with genetic counselors for prospective parents who carry the mutation.